Classical members of the Phospholipase D (PLD) enzyme superfamily play essential roles in signal transduction pathways in many organisms. The most common enzymatic action undertaken by members of this superfamily is to generate the lipid second messenger phosphatidic acid through the hydrolysis of phosphatidylcholine. Cell biological studies have suggested many possible processes in which PLD family members might participate. On the organismal level, however, PLD's physiological and pathophysiological roles are in the early phases of investigation. Initial reports of mice lacking PLD isoforms have revealed phenotypes connected to platelet activation and receptor signaling. An intriguing possibility has arisen, though based on cell biological findings of studies on mice lacking the second isoform, PLD2, and human physiology linked to a PLD2 genetic variant. Taken together, I propose here to study PLD2's potential functions in cardiovascular homeostasis via regulation of plaque formation and blood pressure. Increased levels of circulating low density lipoproteins (LDL) and increased LDL accumulation by macrophages are major factors that leading to plaque formation and ultimately atherosclerosis. Peroxisome proliferator-activated receptor-? (PPAR?) is one of the major players in this process. Recent findings have proposed roles for PLD2 in the regulation of PPAR?; studies now possible using PLD2-/- mice and macrophages in my sponsor's laboratory permit me to explore this relationship with new approaches. Aim 1 will focus on the susceptibility of PLD2-/- macrophages to lipid accumulation and PLD2-/- mice to plaque formation. Aim 2 will explore PLD2's potential contribution to the regulation of blood pressure via its involvement in the renin-angiotensin-aldosterone system. PLD2 has been proposed by my sponsor's lab to regulate endocytosis and signaling efficiency of the Angiotensin II receptor, and a PLD2 polymorphism in humans correlates with decreases in blood pressure. PLD2-/- mice and primary zona glomerulosa cells will be used to delineate the mechanism(s) by which PLD2 affects blood pressure. Ultimately, the knowledge gathered from these experiments will be beneficial to the growing understanding of the development of cardiovascular disease. These studies will also provide information necessary for new pharmacological targets aimed at the prevention of cardiovascular disease risk factors including hypertension and atherosclerosis.